To help detect early and/or mild vitamin B12 deficiency; to help diagnose methylmalonic acidemia, a rare inherited metabolic disorder

When To Get Tested?

When you have a low vitamin B12 level and/or have symptoms of B12 deficiency such as numbness, tingling in the hands or feet, trouble walking, swelling of body tissues, or yellowing of the skin or eyes; as part of newborn screening

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The reference ranges for your tests can be found on your laboratory report. They are typically found to the right of your results.

If you do not have your lab report, consult your healthcare provider or the laboratory that performed the test(s) to obtain the reference range.

Laboratory test results are not meaningful by themselves. Their meaning comes from comparison to reference ranges. Reference ranges are the values expected for a healthy person. They are sometimes called "normal" values. By comparing your test results with reference values, you and your healthcare provider can see if any of your test results fall outside the range of expected values. Values that are outside expected ranges can provide clues to help identify possible conditions or diseases.

While accuracy of laboratory testing has significantly evolved over the past few decades, some lab-to-lab variability can occur due to differences in testing equipment, chemical reagents, and techniques. This is a reason why so few reference ranges are provided on this site. It is important to know that you must use the range supplied by the laboratory that performed your test to evaluate whether your results are "within normal limits."

Methylmalonic acid (MMA) is a substance produced in very small amounts and is necessary for human metabolism and energy production. In one step of metabolism, vitamin B12 promotes the conversion of methylmalonyl CoA (a form of MMA) to succinyl Coenzyme A. If there is not enough B12 available, then the MMA concentration begins to rise, resulting in an increase of MMA in the blood and urine. The measurement of elevated amounts of methylmalonic acid in the blood or urine serves as a sensitive and early indicator of vitamin B12 deficiency.

Over time, vitamin B12 deficiency can cause blood cell changes, leading to anemia and the production of large red blood cells (macrocytes). It can also cause signs and symptoms of neuropathy, such as numbness and tingling in the hands and feet and/or, in advanced cases, mental or behavioral changes such as cognitive impairment, confusion, irritability, and depression. An increased concentration of MMA is often detectable before blood cell changes and before full-blown symptoms are apparent, though some people may have some degree of neuropathy.

The relationship between MMA and B12 has been known for over 40 years, but the use of MMA testing is not widespread nor is there agreement on its clinical utility. Because a relatively large amount of the B12 found in the blood is bound to proteins and is not biologically active, some in the medical community think that MMA may be a better measure of bioavailable B12 than the usual vitamin B12 test. Others believe that MMA and homocysteine (which may also be elevated when either B12 or folate is deficient) are valuable in detecting early and mild cases of B12 deficiency. Still others argue that many of the mild deficiencies detected do not progress to more severe deficiencies and do not necessarily need to be identified or treated.

Testing newborns for high levels of MMA may help diagnose methylmalonic acidemia, a rare metabolic disorder that occurs in about 1 in 25,000 to 100,000 people. Screening for this disorder is part of mandatory programs in all 50 states in the U.S. Babies with this disease are unable to convert methylmalonyl CoA to succinyl CoA. They appear normal at birth, but as they consume protein, they begin to show symptoms such as excessive tiredness, vomiting, dehydration, weak muscle tone, seizures, mental retardation, strokes, and severe metabolic acidosis. For more, see the newborn screening article.

How is the sample collected for testing?

A blood sample is obtained by inserting a needle into a vein in the arm. For newborns, blood may be collected from a heelstick. A single random urine sample may be collected (the second morning sample is preferred) or a 24-hour collection of urine may be requested.

Is any test preparation needed to ensure the quality of the sample?

Fasting is typically required for the MMA blood test. For a random urine sample, the person being tested should fast overnight, discard the first urine sample of the morning, and then collect the second sample.

MMA is a substance produced in very small amounts in the body. It is necessary for metabolism and energy production. In one step of metabolism, vitamin B12 promotes the conversion of methylmalonyl CoA (a form of MMA) to succinyl Coenzyme A. If there is not enough B12 available, then the MMA level begins to rise, resulting in an increase of MMA in the blood and urine. Measuring methylmalonic acid in the blood or urine can help detect early vitamin B12 deficiency.

There are currently no guidelines for screening asymptomatic adults for vitamin B12 deficiency, but confirmation with MMA and/or homocysteine may be necessary for those at high risk without symptoms, such as the elderly, or when certain medications have been taken for a long time.

MMA is a very sensitive test in indicating a B12 deficiency. It is more specific than homocysteine and is the confirmatory test of choice for a B12 deficiency.

Occasionally, specialized MMA testing may be ordered to help diagnose methylmalonic acidemia, a rare inherited metabolic disorder. Newborn screening programs in all 50 states in the U.S. now require testing for this disorder (see Newborn Screening).

MMA is also ordered for asymptomatic adults who have a higher likelihood of having vitamin B12 deficiency, such as the elderly, or for those taking certain drugs, like Metformin, for a long time. An MMA test also may be ordered as a follow-up to an elevated homocysteine level if the two tests are not ordered together.

MMA testing may be ordered when a health practitioner suspects that an acutely ill infant may have inherited methylmalonic acidemia.

If only the homocysteine level is elevated and not MMA, then the person may have a folate deficiency. This distinction is important because giving folate to some who is B12-deficient will treat the anemia but does not treat the neurologic damage, which may be irreversible.

If both MMA and homocysteine levels are normal, then it is unlikely that there is a B12 deficiency.

Moderately to severely elevated levels of MMA may be seen in infants with the rare inherited disease methylmalonic acidemia.

A decreased level of MMA is not common and is not considered clinically significant.

An elevated MMA test may indicate a B12 deficiency, but the amount of MMA measured does not necessarily reflect the severity of the deficiency, its likelihood of progressing, or the presence or severity of any symptoms.

If an individual has kidney disease, he may have a falsely high level of MMA in his blood. If the kidneys are not functioning properly, they cannot properly eliminate MMA in the urine, causing MMA to accumulate in the blood.

Some studies have found a high variation in MMA levels when they are measured over time.

If your B12 test result is in the lower end of the normal range and you do not present with significant clinical symptoms, your healthcare provider may feel that you have adequate B12 and will rely on these findings rather than an elevated MMA. This may be especially true if your homocysteine level is normal. Your healthcare provider may want to monitor your condition over time and may be reluctant to start you on what could be lifelong treatment with B12 injections and/or oral supplementation unless it is truly necessary.

In most cases, it is okay to use blood or urine for this test. Sometimes, a healthcare provider may want to test both blood and urine in order to compare the MMA results. Since homocysteine is a blood test, it may be more efficient and convenient to draw blood for both the MMA and homocysteine tests when they are ordered together.

Genome.gov. NIH National Human Genome Research Institute. Clinical and Basic Investigations of Methylmalonic Acidemia (MMA) and Related Disorders. Available online at http://www.genome.gov/19016900. Accessed September 2015.

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